Therapy Investigated for ALS May Find New Role in Kennedy’s Disease

A growth factor that has generated tides of hope and disappointment for treating amyotrophic lateral sclerosis (ALS) may turn out to be an effective therapy for a less common disease, Kennedy’s disease.

In clinical trials, insulin-like growth factor 1 (IGF-1) failed to show a consistent benefit for people with ALS. Although IGF-1 had promising effects in mice with ALS, the basis for those effects has never been clear. A new study from investigators at the National Institute of Neurological Disorders and Stroke (NINDS) shows that a form of IGF-1 protects mice against Kennedy’s disease by acting on a key pathway involved in the disease.

“IGF-1 might work better and more specifically in Kennedy’s disease than in ALS,” says Kenneth Fischbeck, M.D., chief of the NINDS Neurogenetics Branch and a senior author on the study, which was published in Neuron*.

Kennedy’s disease, also called spinal and bulbar muscular atrophy (SBMA), attacks motor neurons, the nerve cells that control voluntary muscle movement. SBMA causes slowly progressive weakness and swallowing problems, but most patients have a normal lifespan. It is a genetic disorder that almost exclusively affects men.

ALS also attacks motor neurons, but unlike SBMA, it causes rapidly progressive weakness and is usually fatal within five years of diagnosis. It is equally common in men and women. In most cases, there is no known cause and only a small fraction of cases is genetic.

Both diseases lack effective therapy. Various growth factors, including IGF-1, have been investigated for treating ALS. Subcutaneous (under the skin) injections of a form of IGF-1 called Myotrophin showed promise in one large clinical trial, but failed to show benefit in two later trials. IGF-1 has not been tested in patients with SBMA.

In 1991, Dr. Fischbeck and his group found that SBMA is caused by a unique kind of mutation – like a stutter in DNA – that affects the androgen receptor. This protein enables cells to respond to testosterone and other masculinizing sex hormones, collectively known as androgens. The mutations that cause SBMA not only disrupt the normal function of the receptor (causing breast development and infertility in some men), they also render it toxic to motor neurons. Inside the motor neurons of patients with SBMA, the mutant protein disrupts the cells’ internal machinery and accumulates in clumps.

SBMA has been reproduced in mice by giving them a mutant androgen receptor gene. In the new study, Dr. Fischbeck and a team of researchers tested whether they could rescue these mice from SBMA by giving them the gene for a muscle-specific form of IGF-1 (mIGF-1). The mIGF-1 protein is produced by voluntary muscles and acts as a local signal for muscle growth.

Boosting mIGF-1 delayed the onset of SBMA in the mice. It also improved their survival and mobility, and lessened signs of damage to their motor neurons.

The researchers established that these benefits were due to suppression of the mutant androgen receptor’s toxicity. They showed that in mice expressing mIGF-1, there was less accumulation of the mutant receptor in motor neurons and muscle. They also showed that mIGF-1 triggers a series of protein interactions that deactivate the mutant androgen receptor and mark it for destruction.

These results add mIGF-1 to a small arsenal of potential therapies under investigation for SBMA. Since the disease involves a “toxic gain of function” of the androgen receptor, androgen-blocking drugs have been tested in clinical trials, according to Dr. Fischbeck. Promising results have inspired a larger, multi-center clinical trial in Japan led by Gen Sobue, M.D., Ph.D., a professor of neurology at Nagoya University Graduate School of Medicine. (Dr. Sobue’s lab also developed the mouse model of SBMA used in the Neuron study.)

“Our plan is to look at different forms of IGF-1 in the SBMA mouse model and see which works best, and then hopefully take it into clinical trials,” Dr. Fischbeck says. This research might also lead to new formulations of IGF-1 or new ways to deliver it that could be worth testing against ALS, he says.

The lead authors of the Neuron study were Isabella Palazzolo, Ph.D., a research fellow at Massachusetts General Hospital in Boston, and Maria Pennuto, Ph.D., an investigator at the Italian Institute of Technology in Genoa, Italy. At the time of the study, Drs. Palazzolo and Pennuto were visiting fellows in Dr. Fischbeck’s lab.